ICF: Novel small molecule inhibitors for the treatment of CCNE1-amplified cancers
Lead Research Organisation:
Newcastle University
Department Name: Translational and Clinical Res Institute
Abstract
This project aims to take important steps towards developing a drug that will target the Achilles' heel of the cancerous cells found in 1 in 5 patients diagnosed with high grade serous ovarian cancer. Patients with this form of cancer currently have a very poor prognosis, and undergo harsh chemotherapy that provides limited benefits in terms of quality or duration of life.
The vulnerability of the ovarian cancer in these patients arises from the fact that these particular cancer cells have multiple copies of the gene that encodes cyclin E. This results in cyclin E protein being produced at abnormally high levels and as a consequence the cells become addicted to cyclin E for their ability to further divide and survive.
Our structural studies have provided novel insights into how aberrant cyclin E signaling may be prevented with a small molecule inhibitor, which would be selectively toxic to ovarian cancers that are dependent upon this pathway for survival. The project team has extensive expertise in drug discovery and has established the experimental systems needed to develop such inhibitors, with chemical start points being identified. The team has also formed collaborations with clinical experts who specialise in the treatment of aggressive ovarian cancers. Clinicians would be able to easily identify the patients with elevated cyclin E who would benefit from a drug developed for these tumour cells; an example of a personalised medicine.
By the end of the project, the team aims to have developed the inhibitors to a point where they can demonstrate selective effects on ovarian cancer cells with elevated cyclin E levels. This would position the project for further development involving the final optimisation of inhibitors towards a drug that could be developed for clinical use.
The vulnerability of the ovarian cancer in these patients arises from the fact that these particular cancer cells have multiple copies of the gene that encodes cyclin E. This results in cyclin E protein being produced at abnormally high levels and as a consequence the cells become addicted to cyclin E for their ability to further divide and survive.
Our structural studies have provided novel insights into how aberrant cyclin E signaling may be prevented with a small molecule inhibitor, which would be selectively toxic to ovarian cancers that are dependent upon this pathway for survival. The project team has extensive expertise in drug discovery and has established the experimental systems needed to develop such inhibitors, with chemical start points being identified. The team has also formed collaborations with clinical experts who specialise in the treatment of aggressive ovarian cancers. Clinicians would be able to easily identify the patients with elevated cyclin E who would benefit from a drug developed for these tumour cells; an example of a personalised medicine.
By the end of the project, the team aims to have developed the inhibitors to a point where they can demonstrate selective effects on ovarian cancer cells with elevated cyclin E levels. This would position the project for further development involving the final optimisation of inhibitors towards a drug that could be developed for clinical use.
Technical Summary
CCNE1 encodes for the cell cycle regulator cyclin E which binds to cyclin-dependent kinase-2 (CDK2) to drive cells through a G1/S cell cycle transition. Genetic perturbation of CDK2 indicates that its function is not essential for mitosis to complete in normal tissue development and homeostasis. In contrast, tumour cells in which CCNE1 is amplified are critically dependent on CDK2 and cyclin E for survival. Such "oncogene-addiction" to CCNE1 occurs in a significant (~20%) cohort of high-grade serous ovarian cancer (HGSOC) and confers a particularly poor patient outcome to current therapy. Although there have been many attempts to pharmacologically-inhibit CDK2 kinase activity, these have resulted in the development of ATP-competitive inhibitors that do not have sufficient selectivity against other CDKs (involved in essential cellular processes) to exert amplicon-dependent activity.
The current application aims to produce novel small molecule inhibitors that are selectively toxic to CCNE1-amplified tumour cells as a stratified medicine for the treatment of HGSOC. Building on hits from crystallographic fragment screening, we have developed compounds that inhibit cyclin binding to CDK2 at nanomolar concentrations. In cell-line studies, these proof-of-principle molecules display mechanism-dependent modulation of cellular biomarkers, and unique growth inhibitory activity in CCNE1-amplified HGSOC cell-lines relative to control CCNE1-unamplified HGSOC cell-lines. In this hit-to-lead/early lead optimisation phase of the project we will utilise structure-based drug design to improve the pharmaceutical properties of our lead compounds to enable proof-of-concept in vivo in models of CCNE1-amplified HGSOC. This will enable the effect of dose and schedule to be examined to inform optimisation of a candidate molecule for clinical development and guide early clinical trial design.
The current application aims to produce novel small molecule inhibitors that are selectively toxic to CCNE1-amplified tumour cells as a stratified medicine for the treatment of HGSOC. Building on hits from crystallographic fragment screening, we have developed compounds that inhibit cyclin binding to CDK2 at nanomolar concentrations. In cell-line studies, these proof-of-principle molecules display mechanism-dependent modulation of cellular biomarkers, and unique growth inhibitory activity in CCNE1-amplified HGSOC cell-lines relative to control CCNE1-unamplified HGSOC cell-lines. In this hit-to-lead/early lead optimisation phase of the project we will utilise structure-based drug design to improve the pharmaceutical properties of our lead compounds to enable proof-of-concept in vivo in models of CCNE1-amplified HGSOC. This will enable the effect of dose and schedule to be examined to inform optimisation of a candidate molecule for clinical development and guide early clinical trial design.
